Organic bismuth compounds of hydroaromatic endomethylene benzoic acids



Patented Oct. 27, 1936 UNITED STATES PATENT OFFICE ORGANIC BISMUTH COMPOUNDS OF HY- DROAROMATIC ENDOMETHYLENE BEN- ZOIC ACIDS Max Bockmiihl, Walter Pei-sch, and Gustav Ehrhart, Frankfort-on-the-Main-Hochst, Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application November 7, 1933, Serial No. 697,078. In Germany November 8,

7 Claims.

The present invention relates to organic bismuth compounds of hydroaromatic endomethylene benzoic acids.

We have found that the bismuth salts of wholly or partially hydrogenated endo-methylene-benzoic acids possess good chemotherapeutic properties. Suitable acids of the said kind are the endomethylene-benzoic acid obtainable by oxidation of camphene and similar compounds, for instance, the camphenilanic acid of the formula CH: 011C003 or the acid of the following formula CH.COOH i or the homologous acid of the formula In the latter case the unsaturated endo-methylene-carboxylic acids obtained as well as the corresponding saturated endo-methylene-carboxylic acids may be transformed into their bismuth salts. The saturated endo-methylene-carboxylic acids are obtainable from the unsaturated acids by bydrogenation. There may be used for instance, the endo-methylene-hexahydrobenzoic acid of the formula or the endo-methylene-hexahydromethy1benzoic acid of the formula CH on I a \CH CH: CILOO OH or the endo-methylene-hexahydroethylbenzoic acid of the formula 0 Ha OH: I

CILCOOE There may also be used endo-methylene-benzoic acids, wherein the endo-methylene-hydrogen atoms have been exchanged for alkyl groups, for instance, the camphane-carboxylic acids of the formula Beilstein, 4th edition, volume9, page 74) are dis- The monoiodo-endomethylene-hexahydromethyl 1" benzoic acid obtainable by addition'of'hydroge'n iodide to the endo-methylene 2.5 'deltas tetra-' hydro-G-methylbenzoic acid, the corresponding diiodo-endtomethylene-hexahydromethyl-benzoic acid obtainable by addition of iodine to the-same parent acid, the mono-iodo-endomethylene-tetrahydromethyl-benzoic acid obtainable 'by-splitei ting off hydrogen iodide from the diiodo-endo methylene-hexahydromethyl-benzoic acid, finally nitrated, partially or wholly hydrogenated endo-methylene-benzoic acids.

The salts of the formula (R) 313i and those of the formula R.Bi=O, wherein R stands for the radical of a wholly or partially hydrogenated endo-methylene-benzoic acid, are therapeutically valuable compounds. g

They can be obtained by causing a bismuth salt to act upon a whollylor partially hydrogenated endo-methylene-benzoic acid. The new bismuth compounds are amorphous substances which decompose without melting when heated, and are insoluble in water, soluble in ether, chloroform and oils and have a strong bactericidal action especially against spirilli, but only a comparatively small toxicity.

The following examples illustrate the invention: (1) 51 grams of camphenilanic acid (cf.

solved together with 12igrams of caustic soda in 150 cc. of water. The solution is mixed with a solution of 48.5 grams of crystallized bismuth nitrate in 150 ccof glycerine and 300 cc. of water. The white precipitate obtained is washed with water and dried. It is the bismuth salt of the camphenilanic acid, readily soluble in chloro-,

form, benzene, ether and oils, insoluble in water and containing 29.7 per cent. of bismuth (cal culated 29.4 per cent. for (C1oH15O2)3Bi).

(2) 3.5 grams of isocamphenilanic acid (Beilstein, 4th edition, volume 9, page 74) are dissolved in 50 cc. of water together with 22 cc. of N-caustic soda solution.- The. solution is mixed with a solution of 3.5 grams of crystallized bismuth nitrate in cc. of glycerine and. cc. of water. The product is worked up as indicated in Example 1. The colorless bismuth compound has the same physical properties salt of camphenilanic acid.

(3) There are dissolved in 15 cc. of alcohol 152 grams of endo-methylene-2.5-delta3-tetrahydro- G-methylbenzoic acid (obtained from cyclopentadiene and crotonic acid by the method described in Annalen, volume 460, page 117): colorless apparently rhombic tablets melting at 96 C. to 97 (3.). The "solution is neutralized with caustic soda solution and the bismuth salt is precipitated, while stirring and cooling, by adding a solution of 16.2 grams of bismuth nitrate in 46 grams of an aqueous mannite solution of 13 per cent. strength. The resultant white voluminous precipitate is soluble in ether, benzene and olive oil and contains 31.6 per cent. of bismuth; it, therea t e b m t paper. The white precipitate obtained is filtered fore, corresponds with the formula: (Cal-11102) 3181.

(4) 18- grams of camphane-carboxylic acid are dissolved in 100 cc. of N-caustic soda solution. The solution obtained is mixed with a solution of 1'7 grams of bismuth nitrate, 8 grams .of .rnannite and 100 cc. of water. The bismuth salt of camphane-carboxylic acid which is thus precipitated is filtered by suction and washed with .water.

It is readily soluble in ether, chloroform and oils, sparingly soluble in water.

(5). 16.8 grams of camphenilanic acid are dissolvedtogether with 4 grams of caustic soda in 150 cc. of water. Into the solution so obtained ,there are simultaneously introduced, while stirring, a solution of 48.5 grams of crystallized bisrnuth nitrate in 150 cc. of glycerine and 300 cc. of "water .and a solution of 8 grams of caustic soda in 100 cc. of water in such a manner that the liquid always shows an alkaline reaction to litmus by suction, washed with water and then dissolved inbenzene. By evaporating the dried 'filtered benzene solution there is obtained the bismuthoxide salt of camphenilanic acid of the formula CioH15O2.BiO soluble in oil. The product contains 53.3 per cent. of bismuth (theory 53.3 per cent). We claim: V 1. The bismuth salts of acids of the following formula R.COOH in which R. stands for a hydroaromatic hydrocarbon radical of the endomethylene-benzene series, said salts being amorphous substances, insoluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli. 2. The bismuth salts of acids of the following formula R.COOH in which R stands for a wholly hydrogenated hydrocarbon radical of the endomethylene-benzene series, said salts being amorphous substances, insoluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

3. The bismuth salts ofacids of the following formula in which R stands for the radical of a wholly hydrogenated hydrocarbon of the endomethylene-benzenei series substituted by lower alkyl groups, said-salts being amorphous substances, insoluble in water, soluble in: ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

4. The bismuthsalts of the acids of the following formula in which R stands for "the radical of a wholly hydrogenated hydrocarbon 0f the endomethylene-benzene series .substitutedby methyl groups, said compounds being amorphous substances, insoluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

H: P Bi CH: l 011-000- said salt being an amorphous substance, insoluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

6. The bismuth salt of isocamphenilanic acid, said salt being an amorphous substance, insoluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

7. The bismuth salt of camphane-carboxylic acid of the following formula:

said salt being an amorphous substance, in- 15 soluble in water, soluble in ether, chloroform and oils, decomposing without melting when heated and having a strong bactericidal action, especially against spirilli.

MAX BOCKM'UHL. 20 WALTER PERSCH. GUSTAV EHRHAR'I. 

